N-heterocyclic derivatives

ABSTRACT

The present invention relates N-heterocyclic derivatives for treating or preventing neuronal damage associated with neurological diseases. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuing application of co-pending InternationalPatent Application PCT/US00/118492, filed Jul. 6, 2000, which claimspriority of U.S. provisional patent No. 60/142,512, filed Jul. 6, 1999.

TECHNICAL FIELD OF THE INVENTION

The present invention relates N-heterocyclic derivatives for treating orpreventing neuronal damage associated with neurological diseases. Theinvention also provides compositions comprising the compounds of thepresent invention and methods of utilizing those compositions fortreating or preventing neuronal damage.

BACKGROUND OF THE INVENTION

Neurological diseases are associated with the death of or injury toneuronal cells. Typical treatment of neurological diseases involvesdrugs capable of inhibiting neuronal cell death. A more recent approachinvolves the promotion of nerve regeneration by promoting neuronalgrowth.

Neuronal growth, which is critical for the survival of neurons, isstimulated in vitro by nerve growth factors (NGF). For example, GlialCell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophicactivity both, in vivo and in vitro, and is currently being investigatedfor the treatment of Parkinson's disease. Insulin and insulin-likegrowth factors have been shown to stimulate growth of neurites in ratpheochromocytoma PC12 cells and in cultured sympathetic and sensoryneurons [Recio-Pinto et al., J. Neurosci., 6, pp. 1211-1219 (1986)].Insulin and insulin-like growth factors also stimulate the regenerationof injured motor nerves in vivo and in vitro [Near et al., Proc. Natl.Acad. Sci., pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res.,641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF)stimulates neural proliferation [D. Gospodarowicz et al., Cell Differ.,19, p. 1 (1986)] and growth [M. A. Walter et al., Lymphokine CytokineRes., 12, p. 135 (1993)].

There are, however, several disadvantages associated with the use ofnerve growth factors for treating neurological diseases. They do notreadily cross the blood-brain barrier. They are unstable in plasma andthey have poor drug delivery properties.

Recently, small molecules have been shown to stimulate neurite outgrowthin vivo. In individuals suffering from a neurological disease, thisstimulation of neuronal growth protects neurons from furtherdegeneration, and accelerates the regeneration of nerve cells. Forexample, estrogen has been shown to promote the growth of axons anddendrites, which are neurites sent out by nerve cells to communicatewith each other in a developing or injured adult brain [(C. DominiqueToran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp. 169-78(1996); and B. S. McEwen et al., Brain Res. Dev. Brain. Res., 87, pp.91-95 (1995)]. The progress of Alzheimer's disease is slowed in womenwho take estrogen. Estrogen is hypothesized to complement NGF and otherneurotrophins and thereby help neurons differentiate and survive.

Other target sites for the treatment of neurodegenerative disease arethe immunophilin class of proteins. Immunophilins are a family ofsoluble proteins that mediate the actions of immunosuppressant drugssuch as cyclosporin A, FK506 and rapamycin. Of particular interest isthe 12 kDa immunophilin, FK-506 binding protein (FKBP12). FKBP12 bindsFK-506 and rapamycin, leading to an inhibition of T-cell activation andproliferation. Interestingly, the mechanism of action of FK-506 andrapamycin are different. For a review, see, S. H. Solomon et al., NatureMed., 1, pp. 32-37 (1995). It has been reported that compounds with anaffinity for FKBP12 that inhibit that protein's rotomase activitypossess nerve growth stimulatory activity. [Lyons et al., Proc. Natl.Acad. Sci. USA, 91, pp. 3191-3195 (1994)]. Many of these such compoundsalso have immunosuppressive activity.

FK506 (Tacrolimus) has been demonstrated to act synergistically with NGFin stimulating neurite outgrowth in PC12 cells as well as sensoryganglia [Lyons et al. (1994)]. This compound has also been shown to beneuroprotective in focal cerebral ischemia [J. Sharkey and S. P.Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate ofaxonal regeneration in injured sciatic nerve [B. Gold et al., J.Neurosci., 15, pp. 7509-16 (1995)].

The use of immunosuppressive compounds, however, has drawbacks in thatprolonged treatment with these compounds can cause nephrotoxicity [Koppet al., J. Am. Soc. Nephrol., 1, p. 162 (1991)], neurological deficits[P. C. DeGroen et al., N. Eng. J. Med., 317, p. 861 (1987)] and vascularhypertension [Kahan et al., N. Eng. J. Med., 321, p. 1725 (1989)].

More recently, sub-classes of FKBP binding compounds which inhibitrotomase activity, but which purportedly lack immunosuppressive functionhave been disclosed for use in stimulating nerve growth [see, U.S. Pat.No. 5,614,547; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner etal., Proc. Natl. Acad. Sci. USA , 94, pp. 2019-23 (1997); and G. S.Hamilton et al., Bioorg. Med. Chem. Lett., 7, pp. 1785-90 (1997)].

Stimulation of neural axons in nerve cells by piperidine derivatives isdescribed in WO 96/41609. Clinical use of the piperidine and pyrrolidinederivatives known so far for stimulating axonal growth has not beenpromising, as the compounds are unstable in plasma and do not pass theblood-brain barrier in adequate amounts.

Though a wide variety of neurological degenerative diseases may betreated by promoting repair of neuronal damage, there are relatively fewagents known to possess these properties. Thus, there remains a need fornew compounds and compositions that have the ability to either preventor treat neuronal damage associated with neuropathologic diseases.

SUMMARY OF THE INVENTION

The present invention provides compounds having formula (I):

and pharmaceutically acceptable derivatives thereof,

wherein:

X is O, S, C (R¹)₂ or NR¹;

A, B and R¹ are independently E, (C₁-C₁₀)-straight or branched alkyl,(C₂-C₁₀)-straight or branched alkenyl or alkynyl, or (C₅-C₇)-cycloalkylor cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl oralkynyl are optionally and independently replaced with E,(C₅-C₇)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 methylene (—CH₂—)groups in said alkyl, alkenyl, or alkynyl groups are optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O)₂—, ═N—, —N═ or—N(R³)—;

or B and R¹ are independently hydrogen;

wherein R³ is selected from hydrogen, (C₁-C₄)-straight or branchedalkyl, (C₃-C₄)-straight or branched alkenyl or alkynyl, or (C₁-C₄)bridging alkyl, wherein said bridge is formed between the nitrogen atomto which said R³ is bound and any carbon atom of said alkyl, alkenyl oralkynyl to form a ring, and wherein said ring is optionally benzofused;

wherein E is a saturated, partially saturated or unsaturated, oraromatic monocyclic or bicyclic ring system, wherein each ring comprises5 to 7 ring atoms independently selected from C, N, O or S; and whereinno more than 4 ring atoms are selected from N, 0 or S;

wherein 1 to 4 hydrogen atoms in E are optionally and independentlyreplaced with halogen, hydroxyl, hydroxymethyl, nitro, SO₃H,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-straight or branched alkyl,(C₂-C₆)-straight or branched alkenyl, O—[(C₁-C₆)-straight or branchedalkyl], O—[(C₃-C₆)-straight or branched alkenyl], (CH₂)_(n)—N(R⁴) (R⁵),(CH₂)_(n)—NH(R⁴)—(CH₂)_(n)—Z, (CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)—Z, O—(CH₂)_(n)—Z, (CH₂)_(n)—O—Z,S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH,C(O)O—[(C₁-C₆)-straight or branched alkyl], C(O)O—(CH₂)_(n)—Z orC(O)—N(R⁴)(R⁵)

wherein each of R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-straightor branched alkyl, (C₃-C₅)-straight or branched alkenyl, or wherein R⁴and R⁵, when bound to the same nitrogen atom, are taken together withthe nitrogen atom to form a 5 or 6 membered ring, wherein said ringoptionally contains 1 to 3 additional heteroatoms independently selectedfrom N, O or S; wherein said alkyl, alkenyl or alkynyl groups in R₄ andR₅ are optionally substituted with Z.

each n is independently 0 to 4;

each Z is independently selected from a saturated, partially saturatedor unsaturated, monocyclic or bicyclic ring system, wherein each ringcomprises 5 to 7 ring atoms independently selected from C, N, O or S;and wherein no more than 4 ring atoms are selected from N, O or S;

wherein 1 to 4 hydrogen atoms in Z are optionally and independentlyreplaced with halo, hydroxy, nitro, cyano, C(O)OH, (C₁-C₃)-straight orbranched alkyl, O—(C₁-C₃)-straight or branched alkyl,C(O)O—[(C₁-C₃)-straight or branched alkyl], amino, NH[(C₁-C₃)-straightor branched alkyl], or N—[(C₁-C₃)-straight or branched alkyl] ₂;

K is selected from hydrogen, (C₁-C₆)-straight or branched alkyl,(C₂-C₆)-straight or branched alkenyl or alkynyl, wherein 1 to 2 hydrogenatoms in said alkyl, alkenyl or alkynyl is optionally and independentlyreplaced with E;

wherein K is optionally substituted with up to 3 substituents selectedfrom halogen, OH, O—(C₁-C₆)-alkyl, O—(CH₂)n—Z, NO_(2,) CO₂H,C(O)—O—(C₁-C₆)-alkyl, C(O)NR⁴R⁵, NR⁴R⁵ and (CH₂)_(n)—Z;

J and D are taken together with the nitrogen atom, form a 5-7 memberedsaturated or unsaturated heterocyclic ring, wherein up to 3 ring atomsare optionally substituted with a heteroatom selected from O, N, S andS(O₂), wherein 1 to 4 hydrogen atoms in said heterocyclic ring areoptionally and independently replaced with (C₁-C₆)-straight or branchedalkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, oxo, hydroxyl orZ; and wherein any —CH₂— group said heterocyclic ring is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O₂)—, or —N(R³)—; andwherein said heterocyclic ring is optionally fused with E;

wherein R⁶ is hydrogen, E, (C₁-C₆)-straight or branched alkyl,(C₃-C₆)-straight or branched alkenyl or alkynyl; or wherein R⁶ and D aretaken together with the atoms to which they are bound to form a 5 to 7membered ring system wherein said ring optionally contains 1 to 3additional heteroatoms independently selected from O, S, N, NH, SO, orSO₂; and wherein said ring is optionally benzofused.

In another embodiment, the invention provides pharmaceuticalcompositions comprising the compounds of formula (I). These compositionsmay be utilized in methods treating various neurological diseases whichare influenced by neuronal regeneration and axon growth or forstimulating neuronal regeneration in an ex vivo nerve cell. Examples ofsuch diseases include peripheral nerve destruction due to physicalinjury or diseases such as diabetes; physical injuries to the centralnervous system (e.g., brain or spinal cord); stroke; neurologicaldisturbances due to nerve degeneration, such as Parkinson's disease,Alzheimer's disease, and amylotrophic lateral sclerosis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds having formula (I):

and pharmaceutically acceptable derivatives thereof,

wherein:

X is O, S, C (R¹)₂ or NR¹;

A, B and R¹ are independently E, (C₁-C₁₀)-straight or branched alkyl,(C₂-C₁₀)-straight or branched alkenyl or alkynyl, or (C₅-C₇)-cycloalkylor cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl oralkynyl are optionally and independently replaced with E,(C₅-C₇)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 methylene (—CH₂—)groups in said alkyl, alkenyl, or alkynyl groups are optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O)₂—, ═N—, —N═ or—N(R³)—;

or B and R¹ are independently hydrogen;

wherein R³ is selected from hydrogen, (C₁-C₄)-straight or branchedalkyl, (C₃-C₄)-straight or branched alkenyl or alkynyl, or (C₁-C₄)bridging alkyl, wherein said bridge is formed between the nitrogen atomto which said R3 is bound and any carbon atom of said alkyl, alkenyl oralkynyl to form a ring, and wherein said ring is optionally benzofused;

wherein E is a saturated, partially saturated or unsaturated, oraromatic monocyclic or bicyclic ring system, wherein each ring comprises5 to 7 ring atoms independently selected from C, N, O or S; and whereinno more than 4 ring atoms are selected from N, O or S;

wherein 1 to 4 hydrogen atoms in E are optionally and independentlyreplaced with halogen, hydroxyl, hydroxymethyl, nitro, SO₃H,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-straight or branched alkyl,(C₂-C₆)-straight or branched alkenyl, O—[(C₁-C₆)-straight or branchedalkyl], O—[(C₃-C₆)-straight or branched alkenyl], (CH₂)_(n)—N(R⁴) (R⁵),(CH₂)_(n)—NH(R⁴)—(CH₂)_(n)—Z,(CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)—Z, O—(CH₂)_(n)—Z,(CH₂)_(n)—O—Z, S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH,C(O)O—[(C₁-C₆)-straight or branched alkyl], C(O)O—(CH₂)_(n)—Z or C(O)—N(R⁴)(R⁵)

wherein each of R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-straightor branched alkyl, (C₃-C₅)-straight or branched alkenyl, or wherein R⁴and R⁵, when bound to the same nitrogen atom, are taken together withthe nitrogen atom to form a 5 or 6 membered ring, wherein said ringoptionally contains 1 to 3 additional heteroatoms independently selectedfrom N, O or S; wherein said alkyl, alkenyl or alkynyl groups in R₄ andR₅ are optionally substituted with Z.

each n is independently 0 to 4;

each Z is independently selected from a saturated, partially saturatedor unsaturated, monocyclic or bicyclic ring system, wherein each ringcomprises 5 to 7 ring atoms independently selected from C, N, O or S;and wherein no more than 4 ring atoms are selected from N, O or S;

wherein 1 to 4 hydrogen atoms in Z are optionally and independentlyreplaced with halo, hydroxy, nitro, cyano, C(O)OH, (C₁-C₃)-straight orbranched alkyl, O—(C₁-C3)-straight or branched alkyl,C(O)O—[(C₁-C₃)-straight or branched alkyl], amino, NH[(C₁-C₃)-straightor branched alkyl], or N—[(C₁-C₃)-straight or branched alkyl]_(2;)

K is selected from hydrogen, (C₁-C₆)-straight or branched alkyl,(C₂-C₆)-straight or branched alkenyl or alkynyl, wherein 1 to 2 hydrogenatoms in said alkyl, alkenyl or alkynyl is optionally and independentlyreplaced with E;

wherein K is optionally substituted with up to 3 substituents selectedfrom halogen, OH, O—(C₁-C₆)-alkyl, O—(CH₂)n—Z, NO₂ CO₂H,C(O)—O—(C₁-C₆)-alkyl, C(O)NR⁴R⁵, NR⁴R⁵ and (CH₂)_(n)—Z;

J and D are taken together with the nitrogen atom, form a 5-7 memberedsaturated or unsaturated heterocyclic ring, wherein up to 3 ring atomsare optionally substituted with a heteroatom selected from O, N, S andS(O₂), wherein 1 to 4 hydrogen atoms in said heterocyclic ring areoptionally and independently replaced with (C₁-C₆)-straight or branchedalkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, oxo, hydroxyl orZ; and wherein any —CH₂— group said heterocyclic ring is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O₂)—, or —N(R³)—; andwherein said heterocyclic ring is optionally fused with E;

wherein R⁶ is hydrogen, E, (C₁-C₆)-straight or branched alkyl,(C₃-C₆)-straight or branched alkenyl or alkynyl; or wherein R⁶ and D aretaken together with the atoms to which they are bound to form a 5 to 7membered ring system wherein said ring optionally contains 1 to 3additional heteroatoms independently selected from O, S, N, NH, SO, orSO₂; and wherein said ring is optionally benzofused.

According to a preferred embodiment, each of A and B in formula (I) is(C₁-C₁₀) straight or branched alkyl, wherein 1-2 hydrogen atoms in saidalkyl are optionally substituted with E.

In another preferred embodiment, B is hydrogen.

According to a more preferred embodiment, each of A and B in formula (I)is —CH₂—CH₂—E or —CH₂—CH₂—CH₂—E.

According to another preferred embodiment, D in formula (I) is (C₁-C7)straight or branched alkyl, E or [(C₁-C6)-straight or branched alkyl]—E.

According to another preferred embodiment, D is an aromatic monocyclicor bicyclic ring system, wherein each ring comprises 5-7 ring atomsindependently selected from C, N, O or S, and wherein no more than 4ring atoms are selected from N, O or S.

According to another preferred embodiment, D is substituted orunsubstituted phenyl or C₁-C₇ straight or branched alkyl group.

According to another preferred embodiment, K and D, taken together withthe nitrogen atom, form a 5-7 membered heterocyclic ring, optionallycontaining up to 3 additional heteroatoms selected from O, N, S andS(O₂), wherein 1 to 4 hydrogen atoms in said heterocyclic ring areoptionally and independently replaced with (C₁-C₆)-straight or branchedalkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, oxo, hydroxyl orZ; and wherein any —CH₂—group said heterocyclic ring is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O₂)—, or —N(R³)—; andwherein said heterocyclic ring is optionally fused with E;

According to a more preferred embodiment, K and D, taken together withthe nitrogen atom, form a 5-7 membered heterocyclic ring, optionallycontaining up to 3 additional heteroatoms selected from O, N, S andS(O₂), wherein said heterocyclic ring is fused with E.

According to another preferred embodiment, E in formula (I) is amonocyclic or bicyclic aromatic ring system, wherein said ring comprises5-7 ring atoms independently selected from C, N, O or S, and wherein 1to 4 ring atoms are independently selected from N, O or

According to a more preferred embodiments of E include phenyl, napthyl,indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, isothiazolyl, 1,3,4-thiadiazolyl, pyridazinyl,pyrimidinyl, 1,3,5-trazinyl, 1,3,5-trithianyl, benzo[b]furanyl,benzo[b]thiophenyl, purinyl, cinnolinyl, phthalazinyl, isoxazolyl,triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolinyl, indolizinyl,isoindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phnazinyl, phenothiazinyl, phenoxazinyl and benzothiazolyl,wherein E is optionally substituted as described above.

More preferred embodiments of E include phenyl, furyl, thienyl, pyridyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, andbenzothiazolyl, wherein E is optionally substituted as described above.

The compounds of formula (I) may be stereoisomers, geometric isomers orstable tautomers. The invention envisions all possible isomers, such asE and Z isomers, S and R enantiomers, diastereoisomers, racemates, andmixtures of those. It is preferred that the substituent in the 2position have the S configuration.

The compounds of the present invention may be readily prepared usingknown synthetic methods. For example, compounds of formula (I) may beprepared as shown below in Scheme I:

wherein D, J, K, X, x, A and B are as defined in formula (I).

In addition to the above synthetic Schemes, one of skill in the artwould be well aware of other synthetic routes to the compounds of thepresent invention.

According to another embodiment, this invention provides compositionscomprising a compound of formula (I) and a pharmaceutically acceptablecarrier.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxy methylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

In another embodiment, the pharmaceutical composition of the presentinvention is comprised of a compound of formula (I), a pharmaceuticallyacceptable carrier, and a neurotrophic factor.

The term “neurotrophic factor,” as used herein, refers to compoundswhich are capable of stimulating growth or proliferation of nervoustissue. Numerous neurotrophic factors have been identified in the artand any of those factors may be utilized in the compositions of thisinvention. These neurotrophic factors include, but are not limited to,nerve growth factor (NGF), insulin-like growth factor (IGF-1) and itsactive truncated derivatives such as gIGF-1 and Des(1-3)IGF-I, acidicand basic fibroblast growth factor (aFGF and bFGF, respectively),platelet-derived growth factors (PDGF), brain-derived neurotrophicfactor (BDNF), ciliary neurotrophic factors (CNTF), glial cellline-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)andneurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in thecompositions of this invention is NGF.

As used herein, the described compounds used in the pharmaceuticalcompositions and methods of this invention, are defined to includepharmaceutically acceptable derivatives thereof. A “pharmaceuticallyacceptable derivative” denotes any pharmaceutically acceptable salt,ester, or salt of such ester, of a compound of this invention or anyother compound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound of this invention, or ametabolite or residue thereof, characterized by the ability to promoterepair or prevent damage of neurons from disease or physical trauma.

If pharmaceutically acceptable salts of the described compounds areused, those salts are preferably derived from inorganic or organic acidsand bases. Included among such acid salts are the following: acetate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. Also, the basic nitrogen-containinggroups can be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides, such as benzyl andphenethyl bromides and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

The described compounds utilized in the compositions and methods of thisinvention may also be modified by appending appropriate functionalitiesto enhance selective biological properties. Such modifications are knownin the art and include those which increase biological penetration intoa given biological system (e.g., blood, lymphatic system, centralnervous system), increase oral availability, increase solubility toallow administration by injection, alter metabolism and alter rate ofexcretion.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of both a described compound and the optional neurotrophicfactor that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Preferably, the compositions shouldbe formulated so that a dosage of between 0.01-100 mg/kg body weight/dayof the described compound can be administered. If a neurotrophic factoris present in the composition, then a dosage of between 0.01 μg-100mg/kg body weight/day of the neurotrophic factor can be administered toa patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of active ingredients will also depend upon the particulardescribed compound and neurotrophic factor in the composition.

According to another embodiment, this invention provides methods forpromoting repair or preventing neuronal damage in vivo or in an ex vivonerve cell. Such methods comprise the step of treating nerve cells withany of the compounds described above. Preferably, this method promotesrepair or prevents neuronal damage in a patient, and the compound isformulated into a composition additionally comprising a pharmaceuticallyacceptable carrier. The amount of the compound utilized in these methodsis between about 0.01 and 100 mg/kg body weight/day.

According to an alternate embodiment, the method of promoting repair orpreventing neuronal damage comprises the additional step of treatingnerve cells with a neurotrophic factor, such as those contained in thepharmaceutical compositions of this invention. This embodiment includesadministering the compound and the neurotrophic agent in a single dosageform or in separate, multiple dosage forms. If separate dosage forms areutilized, they may be administered concurrently, consecutively or withinless than about 5 hours of one another.

Preferably, the methods of this invention are used to stimulate axonalgrowth in nerve cells. The compounds are, therefore, suitable fortreating or preventing neuronal damage caused by a wide variety ofdiseases or physical traumas. These include, but are not limited to,Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease,Tourette's syndrome, stroke and ischemia associated with stroke, neuralparopathy, other neural degenerative diseases, motor neuron diseases,sciatic crush, spinal cord injuries and facial nerve crush.

In a particularly preferred embodiment of the invention, the method isused to treat a patient suffering from trigeminal neuralgia,glosspharyngeal neuralgia, Bell's Palsy, myasthenia gravis, musculardystrophy, muscle injury, progressive muscular atrophy, progressivebulbar inherited muscular atrophy, herniated, ruptured, or prolapsedinvertebrae disk syndrome's, cervical spondylosis, plexus disorders,thoracic outlet destruction syndromes, peripheral neuropathies, such asthose caused by lead, dapsone, ticks, or porphyria, other peripheralmyelin disorders, Alzheimer's disease, Gullain-Barre syndrome,Parkinson's disease and other Parkinsonian disorders, ALS, Tourette'ssyndrome, multiple sclerosis, other central myelin disorders, stroke andischemia associated with stroke, neural paropathy, other neuraldegenerative diseases, motor neuron diseases, sciatic crush, neuropathyassociated with diabetes, spinal cord injuries, facial nerve crush andother trauma, chemotherapy- and other medication-induced neuropathies,and Huntington's disease.

More preferably, the compositions of the present invention are used fortreating Parkinson's disease, amylotrophic lateral sclerosis,Alzheimer's disease, stroke, neuralgias, muscular atrophies, andGuillain-Barré syndrome.

For use of the compounds according to the invention as medications, theyare administered in the form of a pharmaceutical preparation containingnot only the active ingredient but also carriers, auxiliary substances,and/or additives suitable for enteric or parenteral administration.Administration can be oral or sublingual as a solid in the form ofcapsules or tablets, as a liquid in the form of solutions, suspensions,elixirs, aerosols or emulsions, or rectal in the form of suppositories,or in the form of solutions for injection which can be givensubcutaneously, intramuscularly, or intravenously, or which can be giventopically or intrathecally. Auxiliary substances for the desiredmedicinal formulation include the inert organic and inorganic carriersknown to those skilled in the art, such as water, gelatin, gum arabic,lactose, starches, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The medicinal formulations may also containpreservatives, stabilizers, wetting agents, emulsifiers, or salts tochange the osmotic pressure or as buffers.

Solutions or suspensions for injection are suitable for parenteraladministration, and especially aqueous solutions of the active compoundsin polyhydroxy-ethoxylated castor oil.

Surface-active auxiliary substances such as salts of gallic acid, animalor vegetable phospholipids, or mixtures of them, and liposomes or theircomponents, can be used as carrier systems.

The neurotrophic effect of the compounds of formula (I) of the presentinvention and their physiologically acceptable salts can be determinedby the methods of W. E. Lyons et al., Proc. Natl. Acad. Sci. USA, Vol.91, pp. 3191-3195 (1994) and W. E. Lyons et al., Proc. Natl. Acad. Sci.USA, Vol. 91, pages 3191-3195 (1994).

In order that this invention may be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofhe invention in any way.

EXAMPLE 1

Benzyl bromoacetate (3.8 ml, 24 mmol) was added to a mixture of6,7-dimethoxy-1,2,3,4-tetrahydoisoquinoline hydrochloride(5 g, 21.8mmol)and potassium carbonate (8.29 g, 60 mmol) in 50 ml of dimethylformamide. The mixture was stirred at room temperature for 16 hours. Thereaction was diluted with ethyl acetate and washed with 10% sodiumbicarbonate, water, and brine. The organic layer was dried overanhydrous sodium sulfate and evaporated in vacuo to afford a goldenbrown oil. The crude oil was purified by flash chromatography (SiO2)eluting with 7:3 dichloromethane/ethyl acetate to afford 3.33 g (44%) ofthe title compound as a clear yellow viscous oil: ¹H NMR(CDCl₃)□7.4-7.31 (5H, m), 6.57 (1H, s), 6.47 (1H, s), 5.18 (2H, s), 3.86(3H, s), 3.84 (3H, s), 3.73 (2H, s), 3.46 (2H, s), 2.88 (4H, m).

EXAMPLE 2

Step A:

Synthesis of (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-aceticacid.

10% Palladium/carbon (200 mg) was added to a solution of 1 (920 mg) in20 ml of ethanol. The solution was stirred at room temperature under anatmosphere of hydrogen for 5 hours. The reaction was filtered throughCelite and the filtrated evaporated in vacuo to afford 680 mg of a lightyellow solid of the desired product that was used without purification.

Step B:

The product of Step A (200 mg, 0.79) was suspended in 15 ml ofdichloromethane and 0.5 ml (2.61 mmol) of diisopropylethylamine andcooled to 5 C with an ice bath. Trimethylacetyl chloride (100 □l, 0.79mmol) was added to the heterogeneous mixture dropwise. After 2 hours,compound×(235 mg, 0.711 mmol) in 5 ml of dichloromethane was added tothe homogeneous solution dropwise and the reaction was slowly warmed toroom temperature overnight. The reaction was diluted with 100 ml ofdichloromethane and washed with 1N NaOH, water, and brine. The organiclayer was dried over anhydrous sodium sulfate and evaporated in vacuo toafford a yellow oil that was purified by flash chromatography elutingwith 97:3 (dichloromethane/methanol) to afford 237 mg of 2 as a lightyellow solid: HPLC (C18 column, gradient 0.1% TFA/1% CH₃CN/98.9% H₂O to0.1% TFA/CH₃CN over 28 min at a flow rate of 1 mL/min) RT 8.093 mins.(>99%); MS 565.3 (M+H); ¹H NMR (CDCl₃)δ: 8.48 (2H, d), 8.43 (2H, d),7.53-7.29 (5H, m), 6.98 (2H, d), 6.75 (2H, d), 6.66 (0.5H, s), 6.63(0.5H, s), 6.58 (0.5H, s), 6.51 (0.5H, s), 4.78 (1H, s), 4.67 (1H, s),4.24 (1H, m), 3.91 (3H, s), 3.89 (1.5H, s), 3.83 (1.5H, s), 3.73 (1H,s), 3.58 (1H, s), 3.47 (1H, s), 3.33 (1H, s), 2.91 (2H, m), 2.84 (1H,m), 2.79 (1H, m), 2.58 (2H, t), 2.57-2.43 (2H, m) 2.18-1.78 (4H, m).

What is claimed is:
 1. A compound having formula (I):

and pharmaceutically acceptable derivatives thereof, wherein: X is O; A is phenyl B is hydrogen; wherein 1 to 4 hydrogen atoms in A are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO₃H, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-straight or branched alkyl, (C₂-C₆)-straight or branched alkenyl, O—[(C₁-C₆)-straight or branched alkyl], O—[(C₃-C₆)-straight or branched alkenyl], (CH₂)_(n)—N(R⁴)(R⁵), (CH₂)_(n)—NH(R⁴)—(CH₂)_(n)—Z, (CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)—Z, O—(CH₂)_(n)—Z, (CH₂)_(n)O—Z, S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH, C(O)O—[(C₁-C₆)-straight or branched alkyl], C(O)O—(CH₂)_(n)—Z or C(O)—N(R⁴)(R⁵); wherein each of R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-straight or branched alkyl, (C₃-C₅)-straight or branched alkenyl, or wherein R⁴ and R⁵, when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, O or S; wherein said alkyl, alkenyl or alkynyl groups in R₄ and R₅ are optionally substituted with Z. each n is independently 0 to 4; each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring contains 5 to 7 ring atoms independently selected from C, N, O or S; and wherein no more than 4 ring atoms are selected from N, O or S; wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(O)OH, (C₁-C₃)-straight or branched alkyl, O—(C₁-C₃)-straight or branched alkyl, C(O)O—[(C₁-C₃)-straight or branched alkyl], amino, NH[C₁-C₃)-straight or branched alkyl], or N—[(C₁-C₃)-straight or branched alkyl]₂; K is hydrogen J and D are taken together with the nitrogen atom, form 1,2,3,4-tetrahydroisoquinolin-2-yl ring; wherein 1 to 4 hydrogen atoms in said ring are optionally and independently replaced with (C₁-C₆)-straight or branched alkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z.
 2. A compound having formula:


3. A composition comprising a compound according to claim 1 and a pharmaceutically effective carrier.
 4. The composition according to claim 3, further comprising a neurotrophic factor.
 5. The composition according to claim 4, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives gIGF-1 and Des(1-3)IGF-I, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5).
 6. The composition according to claim 5, wherein said neurotrophic factor is nerve growth factor (NGF).
 7. A method for stimulating neuronal regeneration in a patient or in an ex viva nerve cell, comprising the step of administering to said patient or said nerve cell a compound according to claim 1 or
 2. 8. The method according to claim 7, wherein said compound is administered to a patient and is formulated together with a pharmaceutically suitable carrier into a pharmaceutically acceptable composition.
 9. The method according to claim 8, comprising the additional step of administering to said patient a neurotrophic factor either as part of a multiple dosage form together with said compound or as a separate dosage form.
 10. The method according to claim 9, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives gIGF-1 and Des(1-3)IGF-I, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and neurotrophin 4/5 (NT-4/5).
 11. The method according to claim 10, said neurotrophic factor is nerve growth factor (NGF).
 12. The method according to claim 8, wherein said method is used to treat a patient suffering from stroke and ischemia associated with stroke. 